Nocturnal Enuresis

Objective: To clarify the pathogenesis of nocturnal enuresis. Methods: Overnight simultaneous monitoring of electroencephalogram and cystometrogram, developed in 1985, was the basic method. Results: Nocturnal enuresis was classified into types I, IIa and IIb. In type I, activation of the arousal center functioned correctly, but the development of the function to switch light sleep to complete awakening was immature. In type IIa, activation of the arousal center failed. In type IIb, transmission of the urinary sensation to the upper centrum was ineffective because of the disturbance of bladder function. Conclusion: There is a possibility that a universal concept embracing the various theories for enuresis proposed in the past could be obtained from this theory.


Introduction
Perhaps many of you have a dog. If you have kept a dog from when it was a young puppy, you will have noticed that toilet training him is very easy. You only have to show him where he can go to toilet, and he will go there, whenever he wishes to urinate. It is amazing that he won't go in other places.
I have not kept a monkey, so this information comes from a friend. Apparently, it was very difficult for the monkey to learn where he could go to the toilet. However scolded or entreated, he simply relieved himself wherever he liked. I think this difference between the two types of animal is based upon the difference in environment during the process of evolution. Dogs lived on the ground, where urine was smelt out by enemies, while monkeys lived in trees, where bodily waste had to be got rid of quickly and in a way that did not slow down movements.
Humans branched off from the monkeys but started a life-style on the ground in groups in an early stage of development. In association with this life-style, a new function of awakening by the sensation of having a full bladder during sleep became necessary.
In the case of humans, however, urination occurs in sleep while they are still sucklings. The ability to awaken in response to a full bladder sensation appears gradually and involuntarily in the infant period. In our survey of 2,033 Japanese school children [1], nocturnal enuresis was observed only in 19% at the age of 5 and in 6% at the age of 11. In other words, surprising enough, the large majority of infants have already acquired the function of awakening in response to a full bladder sensation during sleep at the age of 5. By what mechanisms in the body are such activities to do with urination and awakening controlled? Recent investigations in our laboratory, as well as elsewhere, are making some of this clear, although only little by little.

Urine Storage and Discharge of the Bladder
The two contradictory functions of storage and discharge of urine in the bladder are controlled efficiently by the cooperation of the physical properties of the bladder   itself and the nerves controlling that organ. It is well known that the internal pressure in the bladder does not increase on the storage but suddenly increases on the discharge of urine. This preferential action of the bladder has commonly been believed to rely only upon nervous control. However, the physical properties of the bladder in themselves may have a more important role than the nervous control.
In our laboratory, Saitoh [2] originally developed a special device to measure the stress and strain of the bladder wall in vivo, which could be applied directly to the outside of the bladder in dogs ( fig. 1).
A stress-strain curve of the bladder wall was thus obtained by artificial stretching and contraction of the bladder tissues ( fig. 2). The curve had a multifunctional character, which could be simplified in a formula: y = ax n (y: strain, x: stress) If a bladder is simulated as a spherical object like a balloon, consisting of various physical properties as expressed by formula (1), various curves of the internal pressure change caused by the inflation of the object are obtained by a computer process, according to the introduction of a number of values of 'n' into the formula [3]. When n is lower than 2.5, the internal pressure of the object decreases with inflation. In contrast, when n is higher than the value of 3.0, the internal pressure increases rapidly. Only at a setting of n between 2.5 and 3.0, can a flat curve of internal pressure such as that in a living bladder be obtained ( fig. 3). The actual values of n determined by Saitoh [2] in the dog experiment always fell into that range. This evidence indicated that the maintenance of the flat internal pressure of the bladder during storage relied not upon nervous control but upon the physical properties of the bladder itself.
Saitoh advanced his theory of bladder physiology yet another step. He adopted the mechanical model for elastic objects proposed by Glantz ( fig. 4). According to this model, the physical property of the component of the object was simulated using a complex of two springs and one dashpot. The character of a certain object was defined by three factors, ·, ß and Á in the following formula:    where " = strain, ·, ß = factor of elasticity, Á = factor of viscosity, C 1 = velocity of stretch.
The character of the two springs was defined by · and ß, while the dashpot was defined by Á.
If values are introduced into each of the three factors, the internal pressure of a spherical object consisting of such a character can be calculated by computer. Conversely, if any curves of the internal pressure of a spherical object are provided, the three factors of the component of the object can be assumed by computer fitting. Figure 5 shows the data of the three factors on the storage and discharge of urine in the human bladder, assumed from the cystometrogram (CMG) in normal subjects. Note that factor Á, which represented the character of the dashpot, did not change much throughout the process of storage and discharge, in spite of dramatic changes in factors · and ß, which represented the character of the two springs.
One can assume from these findings that the process of storage and discharge of urine could be conducted only by the very simple mechanism of switching the character of the two springs in the Glantz model ( fig. 6). This simple function of switching must be the true role of the nervous control of the bladder. If the switching is completed properly, the other delicate functions involved in the storage and discharge of urine could be activated smoothly only by the physical properties of the bladder.
In an additional comment, the three factors assumed from the CMG in the experimental neurogenic bladder in dogs demonstrated very different data from those in nor-mal subjects ( fig. 7). The pathophysiology of neurogenic bladder could thus be understood as an abnormality of the physical properties of the bladder components.

Development of Urination and Sleep
The flatness of the intravesical pressure on storage is thus thought to be an original characteristic of the bladder. We have performed cystometry on 5 cases of healthy sucklings and obtained a CMG with exactly the same flat pattern as that of adults in all cases ( fig. 8). Although some investigators consider an unstable bladder with uninhibited contractions an 'immature' bladder, our results did not support this concept. An unstable bladder might not be immature, but it is probably a pathologic state with a neurogenic disorder, which even occurs in immature children.
In sucklings, the storage and discharge of urine proceed automatically under the control of the lower urination centrum in the sacral cord. According to our investigation mentioned previously, the afferent stimulation from the bladder to the lower centrum could be a tension of the bladder wall, while the efferent stimulation from the centrum to the bladder could be the switching a physical property of the bladder.
In association with children's development, however, a urinary sensation when the bladder is full is comprehended consciously in the upper centrum, which decides whether urination is timely or not ( fig. 9). It is said that this control of the lower centrum by the upper centrum may be completed before the age of 5 on the average. Children first learn to control urination when awake, then in the next step arouse even during sleep when the bladder becomes full.
On the other hand, the pattern of sleep also changes remarkably with children's development. Immediately after birth, infants sleep more than 16 h a day making no distinction between day and night. Also before the age of 5, such multiphasic sleep turns to a monophasic pattern, in which the child awakens during daytime and sleeps at night. The functions of urination and sleep thus develop with age. When both functions are completed, at the age of 5 on the average, the basic human life-style is established, in which the child sleeps at night and never urinates during sleep.

Mechanism of Arousal by Bladder Filling
To clarify this mechanism in detail, we developed a method of overnight simultaneous monitoring by electroencephalography (EEG) and cystometry (CM) in 1985 [4]. The EEG is a good indicator of sleep patterns, while the CMG represents the altering condition of the bladder. For the EEG, percentile components of ·-, ß-, -and ‰-bands were recorded continuously by a frequency-analyzing EEG trend monitor unit.
When normal subjects fell asleep, the percentage of ‰ soon became dominant on the EEG, indicating deep sleep (stage 3 or 4), and at the same time a flat line was recorded on the CMG, indicating stable intravesical pressure as when awake. While the bladder was being filled, the percentage of ‰-waves decreased, and the -waves increased on the EEG, changing to a pattern of light sleep (stage 1 or 2). About 10-20 min after this change, normal subjects awoke, had a full bladder sensation and proceeded to the toilet to urinate (fig. 10).
The mechanism of this transition from deep sleep to light sleep, when the bladder was full, was elucidated clearly from our experiment in rats. Current physiology and anatomy have revealed that at least four kinds of arousal networks are available in the brain, locus coeruleus (LC) with transmitters of noradrenaline, raphe nuclei with serotonin, tuberomammillary nucleus with histamine or laterodorsal tegmental nucleus with acetylcholine, respectively. Of these, the network of noradrenalineactivating neurons originating in the LC, which is located at the bottom of the fourth cerebral ventricle, is believed to be the most typical activating system for arousal [5].
Male Wistar rats were anesthetized and the head was fixed in a stereotaxic instrument. The LC was punctured with a glass pipette microelectrode to record the neuronal activity of a single LC neuron. The location of the puncture site was confirmed histologically after sacrifice. The EEG and CMG were recorded simultaneously.
In the state of deep anesthesia corresponding to stage 3 or 4 sleep on the EEG, a remarkable increase in the LC discharge rate occurred immediately after bladder distension with 0.5 ml of physiological saline, followed by a change in the EEG pattern from slow to fast waves ( fig. 11). The finding indicated that acute bladder distension caused the LC to be activated, resulting in the transition from deep sleep to light sleep. This corresponded well to the observations made from simultaneous monitoring by EEG and CM in humans.
In the state of light anesthesia corresponding to stage 1 or 2 sleep on the EEG, neither increase in the LC discharge rate nor change in the EEG was observed in response to bladder distension ( fig. 12). This finding suggested that the arousal response of the LC was only effective in switching deep sleep to light sleep, but was not effective after switching [6]. To achieve complete awaken-ing, further motivation seemed to be necessary after the switch from deep sleep to light sleep.
Sleep spindles appearing on the EEG are five or more consecutive waves with a frequency of 11-16 Hz and amplitudes greater than 5 ÌV. The waves are believed to be generated in the thalamus and to represent the function of resuming interrupted sleep and maintaining it [7].
We measured the sleep spindle rate in the transition state from deep sleep to light sleep in humans. When the bladder became full, the ‰-wave rate decreased suddenly, representing an arousal reaction. In association with the decrease of ‰-waves, there was a remarkable increase in sleep spindle rate for several minutes, but then the waves diminished gradually and eventually disappeared. The examinee woke completely and went to the toilet to void ( fig. 13) [6].
As shown here, whenever deep sleep transfers to light sleep, sleep spindles are generated to maintain sleep. To achieve complete awakening after the transition state, the diminution of sleep spindles is mandatory.    Based upon these results, a hypothesis on the mechanism of arousal reaction when the bladder becomes full during sleep was proposed (fig. 14). The information of bladder filling may be transmitted to the LC as urinary sensation and the activation of the LC change deep sleep to light sleep. At that moment, the thalamus indicates complete arousal by diminishing its suppressive activity.

Classification of Enuresis
As nocturnal enuresis is the disorder of involuntary urination while sleeping, the abnormality should lie in the mechanisms of urination or arousal reaction when the bladder is full. In 1989, we proposed a new classification of enuresis into three types: types I, IIa and IIb, according to the pathophysiology of the disease [4].
Before this classification, we exclude enuretic patients with organic disorders like urethral ring, vesicoureteral reflux or neurogenic bladder, by routine urological examinations [8]. Therefore the enuresis classified here is only for monosymptomatic patients without any organic disorders.
The classification is made by overnight simultaneous monitoring by EEG and CM. Up to now, a total of 1,252 cases of nocturnal enuresis without organic disorders have been examined. Approximately 60% of them belong to type I, 10% to type IIa and 30% to type IIb (table 1).
Each type will be discussed in turn, following the mechanism of an arousal reaction. For better comprehension, type IIb is dealt with first. The abnormality in this type is in the ineffective transmission of urinary sensation to the upper centrum, caused by a disturbance in bladder function ( fig. 14).
Type IIb is due to a latent neurogenic bladder disorder that is only manifested during sleep. Continuous uninhibited contraction of the bladder is evident on the CMG after the subject is asleep, although the CMG is fairly normal during daytime. Due to the frequent contractions of the bladder, no proper urinary sensation can reach the upper centrum, resulting in automatically occurring enuresis when the bladder is full, without the activation of the arousal centre ( fig. 15).
Since type IIb is thought to be a kind of latent neurogenic bladder, the first-choice treatment should be anticholinergic drugs to suppress the uninhibited contraction of the bladder. Some patients were cured by this prescription alone, some changed to other types of enuresis with the disappearance of abnormal bladder contractions. The clinical course of 161 patients with enuresis type IIb, who have been reexamined after treatment, is shown in table 2.
Type IIa is the disease of the failure of activation in the arousal center, although the bladder function is correct, generating a proper urinary sensation. In other words, this type is caused by a severe disturbance in arousal ( fig. 14).
On overnight simultaneous monitoring by EEG and CM in type IIa, the CMG is flat throughout the process of bladder filling, as for normal subjects, but the EEG shows no response even when the bladder becomes full and enuresis occurs suddenly in deep sleep ( fig. 16). It is still unclear whether the failure of activation in the arousal center in this type is based upon the dysfunction of the center itself or upon an intentional cancelation of activation by an unknown mechanism.
It is worth noting that the rate of abnormal findings in EEG was significantly higher in type IIa, as compared to that in the other two types (table 3). Paroxysmal discharge consists of focal spikes or spike-and-wave, which is specified as waves recognized in epilepsy. Since the relation between epilepsy and nocturnal enuresis has been discussed from many years ago, there is a possibility that latent epilepsy might be one of the pathophysiological factors in this type of enuresis.
For the treatment of patients with enuresis type IIa, those who showed distinct signs of latent epilepsy were treated by antiepileptic drugs. The other patients were prescribed tricyclic antidepressants. Some of them were cured by these treatments, while others changed to enuresis type I with an arousal reaction on the EEG within a few months or up to a few years. The clinical courses of 63 patients with enuresis type IIa are shown in table 4.
Enuresis type I is the most common type, making up approximately 60% of the total number of enuresis patients, and is caused by a mild disturbance in arousal. The activation of the arousal center proceeds correctly, but the development from light sleep to complete awakening is not achieved properly ( fig. 14).
When the bladder becomes full during deep sleep (stage 3 or 4), evidence of arousal appears on the EEG: the EEG pattern changes to that for stage 1 or 2 sleep. However, about 5-15 min after this change, enuresis occurs without the patient awakening ( fig. 17). The mechanism could be explained by saying that both bladder function and EEG reaction were already established, but the final stage of awakening was incomplete.
According to our investigation, the rate of sleep spindles diminished after the transition from deep sleep to light sleep when the bladder was full in healthy subjects,  Fig. 15. EEG and CMG during sleep and bed-wetting in a patient with enuresis type IIb.  as shown in figure 13. In patients with enuresis type I, however, the rate of sleep spindles increased remarkably during transition but they did not diminish subsequently. Such a state persisted for 20-30 min and then the ‰-wave rate began to increase again. Enuresis occurred at this time without the patient awakening ( fig. 18).
As mentioned previously, the function of sleep spindles is believed to be resumption of interrupted sleep. In the healthy condition, sleep spindles diminish to allow complete awakening. In contrast, in enuresis type I, the transition state from deep sleep to light sleep caused by bladder filling returned to deep sleep with the frequent generation of sleep spindles. Enuresis occurred in this drowsy state.
The pathogenesis of enuresis type I was that the final stage of awakening was incomplete, resulting in involuntary urination while the patient was not sufficiently conscious. The optimal treatment for enuresis type I should therefore be to make patients learn how to wake completely when the stage of sleep changes from deep to light sleep soon after the bladder is full. We developed an original therapeutic device using consecutive EEG monitoring which buzzes an alarm at the point at which the stage of sleep changes ( fig. 19). This machine was included in the category of already established conditioning treatments, but its function is completely different from conventional enuresis alarms on the market, in which the subject is alerted after enuresis. Our machine buzzes before enuresis has occurred. Fig. 19. Therapeutic device in use. Fig. 20. Ultrasonograms of the bladder by automatic bladder volumeter. The transition from deep sleep to light sleep is also seen in the state of REM sleep. To avoid buzzing in the REM state, we recently developed an automatic volumeter for the bladder by means of an ultrasonograph attached to the lower abdomen of the examinee (fig. 20). The volumeter was connected electronically to the therapeutic device to alert the subject only when the bladder was full. The set of machines will soon be commercially available.
The treatment using our therapeutic device was usually performed consecutively for 5-6 nights by admitting the patient to hospital. From 1987 to 1996, 430 patients with enuresis type I were treated in this way in our clinic. Out of these, 57 cases (13%) were cured, in 198 cases (46%) the treatment was effective and 175 cases (41%) were unchanged (table 5). The effective rate was approximately 60%.

Conclusion
There have been a variety of theories on the pathogenesis of nocturnal enuresis. Many of them seemed to be partly true but had some weak points, failing to explain all the findings on enuresis. Our theory presented here is still an on-going idea, but it may have the potential of becoming a universal concept embracing the various theories proposed in the past.